Differential display cloning of a novel human histone deacetylase (HDAC3) cDNA from PHA-activated immune cells.
The nucleosomal histones can be modified through reversible acetylation by histone acetyltransferases (HATs) and deacetylases (HDACs). HATs induce nucleosomal relaxation and allow DNA-binding by transcriptional activators. HDACs from corepressor complexes which negatively regulate cell growth. However, the HDAC inhibitors butyrate and Trichostatin A block T cell proliferation, suggesting that not all effects of HDACs lead to repression. Using mRNA differential display and 5'RACE we isolated human HDAC3, a novel gene that is upregulated in PHA-activated T cell clones. HDAC3 is homologous to other human HDACs and yeast RPD3. In peripheral blood mononuclear cells (PBMCs), activation by PHA, PMA and alpha-CD3 increased HDAC mRNA but no effect was seen with IFN-gamma, LPS, or IL-4. In contrast, GMCSF downregulated PBMC levels of HDAC3 mRNA. All HDACs were found to be ubiquitously expressed in immune and non-immune tissues. In human myeloid leukemia THP-1 cells, HDAC3 transfection resulted in increased size, aberrant nuclear morphology and cell cycle G2/M cell accumulation. Functional activity of the expressed HDAC3 protein was confirmed in alpha-HDAC3 antibody immunoprecipitates by a histone deacetylase assay. Our study suggests the participation of HDACs in cell cycle progression and activation.
Dangond
F
F
Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. dangond@cnd.bwh.harvard.edu
Hafler
D A
DA
Tong
J K
JK
Randall
J
J
Kojima
R
R
Utku
N
N
Gullans
S R
SR
D000595:Amino Acid Sequence; D015152:Blotting, Northern; D017252:CD3 Complex; D002453:Cell Cycle / Q000502:physiology; D003001:Cloning, Molecular; D004247:DNA / Q000032:analysis; D005434:Flow Cytometry; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006655:Histone Deacetylases / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D010802:Phylogeny; D010835:Phytohemagglutinins / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D013601:T-Lymphocytes / Q000201:enzymology*; D014162:Transfection / Q000235:genetics; D014407:Tumor Cells, Cultured; D000099186:Histone Deacetylase 3
D017252:CD3 Complex; D004247:DNA; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006655:Histone Deacetylases; D010835:Phytohemagglutinins; D012333:RNA, Messenger; D000099186:Histone Deacetylase 3